BASIC AND EXPERIMENTAL RESEARCH Sotrastaurin (AEB071) Alone and in Combination With Cyclosporine A Prolongs Survival Times of Non- Human Primate Recipients of Life-Supporting Kidney Allografts Marc Bigaud, 1,4 Grazyna Wieczorek, 1 Christian Beerli, 1 Maxime Audet, 2 Antoine Blancher, 3 Christoph Heusser, 1 Randall E. Morris, 1 and Ju ¨rgen Wagner 1 Background. Sotrastaurin (STN), a novel oral protein kinase C inhibitor that inhibits early T-cell activation, was assessed in non-human primate recipients of life-supporting kidney allografts. Methods. Cynomolgus monkey recipients of life-supporting kidney allografts were treated orally with STN alone or in combination with cyclosporine A (CsA). Results. STN monotherapy at 50 mg/kg once daily prolonged recipient survival times to the predefined endpoint of 29 days (n=2); when given at 25 mg/kg twice daily, the median survival time (MST) was 27 days (n=4). Neither once-daily monotherapy of STN 20 mg/kg nor CsA 20 mg/kg was effective (MST 6 days [n=2] and 7 days [n=5], respectively). In combination, however, STN 20 mg/kg and CsA 20 mg/kg prolonged MST to more than 100 days (n=5). By combining lower once-daily doses of STN (7 or 2 mg/kg) with CsA (20 mg/kg), MST was more than 100 (n=3) and 22 days (n=2), respectively. Neither in single-dose pharmacokinetic studies nor the transplant recipients were STN or CsA blood levels for combined treatment greater than when either drug was administered alone. STN blood levels in transplant recipi- ents during combination therapy were dose related (20 mg/kg, 30 –182 ng/mL; 7 mg/kg, 7– 41 ng/mL; and 2 mg/kg, 3–5 ng/mL). STN at a daily dose of up to 20 mg/kg was relatively well tolerated. Conclusions. STN prolonged survival times of non-human primate kidney allograft recipients both as monotherapy and most effectively in combination with CsA. Pharmacokinetic interactions were not responsible for the potentiation of immunosuppressive efficacy by coadministering STN and CsA. Keywords: AEB071, Immunosuppression, Kidney, Non-human primate, Sotrastaurin, Protein kinase C, Transplant. (Transplantation 2012;93: 156–164) T he use of current immunosuppressive agents to prevent solid organ allograft rejection is frequently restricted by insufficient efficacy and mechanism-based adverse effects, leading to intense interest in new agents with an improved therapeutic index (1, 2). Modulation of the T- and B-cell sig- naling pathways through inhibition of protein kinase C (PKC) isoforms (3–6) has recently been proposed as a novel immunosuppressive approach that could potentially reduce the need for calcineurin inhibitors (CNIs) therapy with their associated toxicities (7). Sotrastaurin (STN) is the first in a new class of selective oral PKC inhibitors (8) that offers highly potent inhibition of early T-cell activation, with novel mechanisms of action that may complement those of CNI (9). The immunosuppressive efficacy of oral STN has been previously demonstrated in rat models of local graft versus host reaction and heart transplan- tation (Tx), and a synergy with other immunosuppressive This work was supported by Novartis Pharma AG, Basel, Switzerland. M.B., G.W., C.B., C.H., R.E.M., and J.W. were employees of Novartis Pharma AG during the study. M.A. and A.B. have served as consultants for No- vartis Pharma AG. 1 Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland. 2 Service de Chirurgie Ge ´ne ´rale et de Transplantation, Ho ˆ pital de Hautepi- erre, Strasbourg, France. 3 Laboratoire d’Immunoge ´ne ´tique Mole ´culaire, EA 3034, Faculte ´ de Me ´de- cine Purpan, Universite ´ Paul Sabatier, Toulouse 3, IFR150 INSERM, CHU de Toulouse, France. 4 Address correspondence to: Marc Bigaud, Ph.D., Novartis Institutes for Biomedical Research (NIBR), Novartis Pharma AG, Novartis Campus, CH-4056 Basel, Switzerland. E-mail: marc.bigaud@novartis.com M.B. was the scientific leader of the non-human primate transplantation program in NIBR and selected the donor/recipient pairs; G.W. per- formed necropsies and all histopathologic evaluations; C.B. performed analytics for drug blood levels; M.A. performed the surgical procedures; A.B. undertook the ABO and DRBexon2 typing; and C.H., R,E.M., and J.W. contributed to the study design and provided scientific support. Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are pro- vided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com). Received 21 February 2011. Revision requested 9 March 2011. Accepted 12 October 2011. Copyright © 2012 by Lippincott Williams & Wilkins ISSN 0041-1337/12/9302-156 DOI: 10.1097/TP.0b013e31823cf92f 156 | www.transplantjournal.com Transplantation • Volume 93, Number 2, January 27, 2012